Disruption of Pre-Bötzinger Complex neuropeptidergic tonality controls fear and metabolic response

Stress profoundly impacts systemic metabolism, yet the central circuits linking stress responses to peripheral metabolic regulation remain poorly defined. Here, we identify the preBötzinger complex (preBötC), a brainstem breathing rhythm generator, as a key stress-responsive hub coordinating metabolic adaptations. Using viral tracing, we show that preBötC neurons project to brown adipose tissue and liver, and that a subset of these projection neurons expresses the pituitary adenylate cyclase–activating polypeptide (PACAP) receptor PAC1R, positioning PACAP signaling as a critical modulator of this circuit. Whole-brain c-Fos mapping revealed robust preBötC activation under stress, while spatial transcriptomics demonstrated altered neuronal metabolic circuitry in preBötC following PAC1R ablation. PAC1R knockdown in preBötC combined with stress resulted in blunted respiratory rhythmicity, reduced sympathetic innervation, and suppression of energy expenditure and lipid metabolic pathways in brown fat, while reprogramming hepatic transcriptional networks toward amino acid metabolism and gluconeogenesis. These findings define a unique neuropeptidergic brainstem–periphery circuit integrating stress, respiration, and metabolism. RNA-seq was performed on BAT and liver isolated from Ctrl (AAV-GFP) or Cre (AAV-Cre) preBötC-injected Adcyap1r1^flox/flox mice subjected to SEFL.

应激可深刻影响全身代谢，但介导应激反应与外周代谢调控的中枢神经环路机制仍尚不明确。本研究确认，前包钦格复合体（preBötzinger complex, preBötC）——脑干呼吸节律发生器——是协调代谢适应的关键应激响应中枢枢纽。通过病毒示踪技术，我们发现preBötC神经元可投射至棕色脂肪组织（brown adipose tissue, BAT）与肝脏，且该类投射神经元的一个亚群表达垂体腺苷酸环化酶激活肽（pituitary adenylate cyclase–activating polypeptide, PACAP）受体PAC1R，由此提示PACAP信号通路是该环路的关键调控因子。全脑c-Fos映射结果显示，应激状态下preBötC被显著激活；而空间转录组学分析表明，敲除PAC1R后preBötC内的神经元代谢环路发生显著改变。在preBötC中敲低PAC1R并联合应激刺激，会导致呼吸节律减弱、交感神经支配减少，并抑制棕色脂肪的能量消耗与脂质代谢通路，同时使肝脏转录网络重编程为偏向氨基酸代谢与糖异生的模式。本研究结果揭示了一条独特的神经肽能脑干-外周环路，可整合应激、呼吸与代谢信号。本研究对经SEFL处理、且preBötC注射了对照腺相关病毒（AAV-GFP）或Cre重组酶腺相关病毒（AAV-Cre）的Adcyap1r1^flox/flox小鼠的棕色脂肪组织（BAT）与肝脏样本开展了RNA测序。